1. Field of the Invention
The present invention relates to processes for preparing compound represented by formula (I) and pharmaceutically acceptable salts thereof:
The present invention also relates to intermediates which are useful in the process.
2. Discussion of the Background
Alzheimer's disease is a neurodegenerative disorder characterized from a histopathologic point of view by a diffuse presence of extracellular and perivascular neuritic plaques and intracellular neurofibrillary tangles in the cerebral parenchyma of Alzheimer patients. Neuritic plaques are mainly composed of aggregates of a protein with 39-43 amino acid residues known as β-amyloid (βA), and, depending on the numbers of amino acids, Aβ39, Aβ40, Aβ42 and Aβ43.
Compounds have been reported which can reduce the production of the most neurotoxic isoform of β-amyloid, namely the form containing 42 amino acids (Aβ42), through their interaction with a macromolecular/multiprotein enzymatic complex with aspartyl-protease activity, known as γ-secretase. In particular WO 2004/074232 discloses derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid of general formula (I):
wherein X and R are defined below, which are capable of modulating γ-secretase activity without affecting other important metabolic processes such as cyclooxygenase-enzymes activity.
The key step of the preparation of said compounds is the Suzuki reaction between a suitable phenylboronic acid or an ester thereof with a 3,4-dihalo-cyclopropane-carboxylic acid. In WO 2004/074232, 3,4-dihalo-cyclopropanecarboxylic acid is obtained starting from 3,4-dihalo-toluene which is transformed into the corresponding benzylbromide by radical bromination in carbon tetrachloride (CCl4); the resulting bromide is transformed into the 3,4-dihalophenylacetonitrile; the latter one is reacted with 1,2-dibromoethane to give the corresponding 3,4-dihalophenylcyclopropanenitrile which is finally hydrolyzed to the desired 3,4-dihalo-cyclopropanecarboxylic.
However, the process described in WO 2004/074232 gives rise to a low overall yield (12-14%) and suffers from severe restrictions for the industrial use. For example, the radical bromination step gives rise to a significant amount of the bis-halogenated side-product, detrimental to its yield, and involves the use of CCl4 which is highly toxic and also both ozone-depleting and a greenhouse gas. In addition, the final Suzuki coupling reaction has a poor yield and the resulting product is difficult to purify by crystallization without a loss of yield. For example, silica gel chromatography has been used for such purification, but scale-up of silica gel chromatography is tedious and requires large volumes of solvents.
Thus, there remains a need for an alternative process of making 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid compounds of formula (I).